Can a patient with opioid use disorder take methadone (opioid agonist) and naltrexone (opioid antagonist) together?

Can a Patient Take Methadone and Naltrexone Together?

No, a patient cannot take methadone and naltrexone together—this combination is explicitly contraindicated and dangerous. Naltrexone will precipitate severe opioid withdrawal in patients taking methadone and block methadone's therapeutic effects. 1

Why This Combination Is Contraindicated

FDA Contraindication

• Naltrexone is absolutely contraindicated in patients currently maintained on opioid agonists such as methadone. 1
• The FDA label explicitly states that naltrexone cannot be given to "patients currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone)." 1
• Administering naltrexone to a patient on methadone will precipitate severe withdrawal that may require hospitalization. 1

Mechanism of the Problem

• Naltrexone is a competitive mu-opioid receptor antagonist that blocks all opioid effects at the receptor level. 2
• When naltrexone is given to someone taking methadone, it displaces methadone from opioid receptors and immediately precipitates withdrawal symptoms. 1
• Patients transitioning from methadone to naltrexone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks after stopping methadone. 1

The Correct Treatment Algorithm for Opioid Use Disorder

First-Line Treatment Options (Choose One, Not Both)

• Methadone or buprenorphine are first-line treatments with the strongest evidence for reducing mortality, opioid use, and HIV/hepatitis C transmission while increasing treatment retention. 3, 4, 5
• Methadone has the strongest evidence for effectiveness and should be offered as medication-assisted treatment in combination with behavioral therapies. 3, 5
• Naltrexone is a second-line option reserved for highly motivated patients who prefer opioid-free treatment and cannot or will not take methadone or buprenorphine. 3, 2

When Naltrexone Can Be Considered

• Naltrexone (oral or long-acting injectable) can be used in nonpregnant adults with opioid use disorder who are highly motivated and prefer opioid-free treatment. 3
• The patient must be completely opioid-free for a minimum of 7-10 days before starting naltrexone to avoid precipitating withdrawal. 1
• For patients transitioning from methadone specifically, they may need to be opioid-free for up to 2 weeks due to methadone's long half-life. 1

Switching from Methadone to Naltrexone (If Absolutely Necessary)

Critical Safety Protocol

• There are no systematically collected data on switching from methadone to naltrexone, and postmarketing case reports indicate severe manifestations of precipitated withdrawal can occur. 1
• The patient must completely discontinue methadone and remain opioid-free for at least 7-10 days, potentially up to 2 weeks. 1
• Healthcare providers must be prepared to manage withdrawal symptomatically with non-opioid medications during this transition period. 1

Naloxone Challenge Test Required

• Before administering naltrexone, perform a naloxone challenge test to confirm the patient is no longer opioid-dependent. 1
• Do not perform the naloxone challenge in patients showing clinical signs of opioid withdrawal or whose urine contains opioids. 1
• If withdrawal signs occur during the naloxone challenge, naltrexone treatment should not be attempted and the challenge can be repeated in 24 hours. 1

Managing the Transition

• Clonidine (an α2-adrenergic agonist) can be used to manage withdrawal symptoms during the transition from methadone to naltrexone. 2, 6
• One study showed clonidine combined with gradually increasing naltrexone doses allowed 91% of patients to withdraw from methadone over 6 days, though this requires controlled inpatient conditions. 6

Common Pitfalls to Avoid

• Never administer naltrexone to a patient currently taking methadone—this will precipitate severe withdrawal and potentially cause treatment dropout. 7, 2
• Do not underestimate the opioid-free period required; methadone's long half-life means patients may still be opioid-dependent even after stopping for several days. 1
• Do not use naltrexone in pregnant women with opioid use disorder; offer methadone or buprenorphine (without naloxone) instead, as these have been associated with improved maternal outcomes. 3
• Recognize that patients who discontinue naltrexone have increased risk of opioid overdose and death due to decreased opioid tolerance. 2

Evidence-Based Treatment Hierarchy

• Methadone and buprenorphine remain the gold standard for opioid use disorder treatment, with methadone having the strongest evidence for effectiveness. 3, 5
• Longer duration of treatment with methadone or buprenorphine allows restoration of social connections and is associated with better outcomes. 5
• Naltrexone is harder to initiate than opioid agonists because of the required abstinence period, but among those who successfully start it, naltrexone can reduce opioid use and craving. 4
• All medication-assisted treatment must be combined with behavioral therapies, as medication alone is insufficient for optimal outcomes. 3, 7